Abstract
Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.
Highlights
Specialty section: This article was submitted to Neurogenomics, a section of the journal Frontiers in Neuroscience
Numerous viral vector types have been tested in clinic, including vaccinia, measles, vesicular stomatitis virus (VSV), polio, reovirus, adenovirus, lentivirus, γ-retrovirus, herpes simplex virus (HSV) and adenoassociated virus (AAV) (Lundstrom, 2018)
It has been shown that the repeat-containing transcripts can be translated into dipeptide repeat proteins (DPRs) even in the absence of an ATG start codon and even though the mutation is in a non-coding region of chromosome 9 open reading frame 72 (C9orf72)
Summary
Gene therapy is an emerging therapeutic tool used to deliver functional genetic material to cells in order to correct a defective gene. Different physical and chemical systems can be applied to deliver therapeutic genes to cells without the need of a viral vector. Due to the fact that high therapeutic doses are required when using non-viral technologies, and the resulting gene expression is generally transient, most gene therapies rely on viral vectors. Adeno-associated virus belongs to the Parvoviridae family and is preferred for gene therapy because it is non-replicating (AAV requires a helper virus for replication), has a low. Recombinant AAV (rAAV) can be produced by replacing the Rep and Cap genes with an expression cassette containing a therapeutic gene of interest (Figure 1B). Formation of wild-type AAV is prevented by expressing the Rep and Cap genes on a separate plasmid (AAV packaging plasmid or AAV helper plasmid). A single administration results in long-term, potentially life-long, gene expression which is a main advantage when in vivo AAV administration requires invasive procedures
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